Scientific Opinion on the substantiation of health claims related to alpha-cyclodextrin and reduction of post-prandial glycaemic responses
(ID 2926, further assessment) pursuant to Article 13(1) of Regulation (EC) No 1924/2006[sup]1[/sup]
EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA)2, 3
European Food Safety Authority (EFSA), Parma, Italy
ABSTRACT
Following a request from the European Commission, the Panel on Dietetic Products, Nutrition and Allergies was asked to provide a scientific opinion on a health claim pursuant to Article 13.1 of Regulation (EC) No 1924/2006 in the framework of further assessment related to alpha-cyclodextrin and reduction of post-prandial glycaemic responses. The food constituent that is the subject of the claim, alpha-cyclodextrin, is sufficiently characterised. The claimed effect, reduction of post-prandial glycaemic responses (as long as post-prandial insulinaemic responses are not disproportionally increased), may be a beneficial physiological effect. The proposed target population is individuals who wish to reduce their post-prandial glycaemic responses. In weighing the evidence, the Panel took into account that two intervention studies showed a significant effect of alpha-cyclodextrin added to starch on post-prandial glycaemic responses without disproportionally increasing post-prandial insulinaemic responses, that one study on alpha-cyclodextrin added to sucrose did not show an effect on post-prandial glycaemic responses, and that there is some evidence in support of a plausible mechanism by which alpha- cyclodextrin could exert the claimed effect. On the basis of the data presented, the Panel concludes that a cause and effect relationship has been established between the consumption of alpha-cyclodextrin with starch-containing meals and reduction of post-prandial glycaemic responses. The Panel considers that in order to obtain the claimed effect, at least 5 g of alpha-cyclodextrin per 50 g of starch should be consumed. The target population is adults who wish to reduce their post-prandial glycaemic responses.
© European Food Safety Authority, 2012
3. Naukowe uzasadnienia wpływu na zdrowie człowieka - Ograniczenie wzrostu stężenia glukozy (glikemii) po posiłku
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Spożycie alfa-cyklodekstryny przyczynia się do ograniczenia wzrostu stężenie glukozy (glikemii) po posiłkach zwierających skrobię
In its earlier opinion (EFSA Panel on Dietetic Products Nutrition and Allergies (NDA), 2010), the Panel considered one human intervention study on the effect of alpha-cyclodextrin on post-prandial glycaemic responses (Buckley et al., 2006) and an unpublished project report which only contained the description of a study but not the results (Diamantis and Bär, 2002a). Based on the information initially provided, the Panel concluded that the evidence was insufficient to establish a cause and effect relationship between the consumption of alpha-cyclodextrin and reduction of post-prandial glycaemic responses (EFSA Panel on Dietetic Products Nutrition and Allergies (NDA), 2010).
In the framework of further assessment, 11 additional studies (Comerford et al., 2011; Diamantis and Bär, 2002b; Gentilcore et al., 2011; Grunberger et al., 2007; Koukiekolo et al., 2001; Li et al., 2009; Ochiai et al., 2008; Oudjeriouat et al., 2003; Shimazu et al., 2009; Weyer et al., 2001; Yun et al., 2009) were provided. Two human intervention studies (Comerford et al., 2011; Grunberger et al., 2007) investigated the effects of alpha-cyclodextrin on health outcomes (e.g. blood lipids, weight loss, and body weight) other than post-prandial glycaemic responses; two human intervention studies (Ochiai et al., 2008; Shimazu et al., 2009) addressed the effects of an anti-diabetic medication (i.e. acarbose) on adiponectin levels; two papers (Weyer et al., 2001; Yun et al., 2009) described the relationship between plasma adiponectin concentrations and insulin sensitivity and insulinaemia in obesity and/or type 2 diabetes; and one systematic review (Li et al., 2009) examined the association between plasma adiponectin levels and incidence of type 2 diabetes. The Panel considers that no conclusions can be drawn from these references for the scientific substantiation of the claim.
This evaluation is based on the scientific references provided in the present and the previous submission which addressed the effects of alpha-cyclodextrin on post-prandial glycaemic responses, and the mechanisms by which alpha-cyclodextrin could exert the claimed effect in the target population.
In the study by Buckley et al. (2006), the effects of boiled white rice with 50 g of digestible carbohydrates, to which 0, 2, 5 or 10 g of alpha-cyclodextrin were added, on post-prandial glycaemic and insulinaemic responses were investigated in 10 healthy subjects (five females), using a double-blind, randomised cross-over design. All subjects received the four test meals on a single occasion, after an overnight fast, with a wash-out period of two days. Blood glucose and insulin concentrations were measured at baseline and over a 2 h period after the ingestion of each meal. Repeated measures analysis of variance (RM-ANOVA) followed by pair-wise comparison of the means by using a test of least significant differences was used to determine the effects of the treatment. The incremental area under the curve (iAUC) for the glucose response was significantly lower for the boiled white rice to which 5 g (mean±SEM -20.4±15.4%; p=0.03) or 10 g (mean±SEM - 49.6±9.9%; p=0.001) alpha-cyclodextrin was added compared to the control rice (without alpha- cyclodextrin). No effect on post-prandial serum insulin concentrations was observed for either dose of alpha-cyclodextrin. The Panel notes that this study shows a dose-dependent effect of alpha- cyclodextrin on reduction of post-prandial glycaemic responses without disproportionally increasing post-prandial insulinaemic responses.
The unpublished study by Diamantis and Bär (2002b) was a single-blind, cross-over study in 12 healthy males (age 23-24 years and mean weight of 73.3 kg) to determine the effect of alpha-cyclodextrin on the glycaemic and insulinaemic response to starch. Subjects consumed either 100 g white bread (providing 50 g starch) together with 0 or 10 g alpha-cyclodextrin or 25 g alpha- cyclodextrin alone (alpha-cyclodextrin was dissolved in 250 ml water) in fasting conditions, with a wash-out period of at least two days. Blood glucose and serum insulin concentrations were measured before and up to 180 min after the consumption of the meal. The glycaemic response of alpha- cyclodextrin and of white bread with alpha-cyclodextrin was 4.3 % and 43 % relative to that of the bread alone (100 %), respectively. The insulinaemic response of white bread with alpha-cyclodextrin was 45 % relative to that of the bread alone (100 %). The iAUC for blood glucose concentrations was significantly lower after consumption of the starch together with 10 g alpha-cyclodextrin compared to
the control (starch without alpha-cyclodextrin) (-58.63%; mean±SEM: 1543.5±469.6 vs. 3731.2±581.9 mg/dl/min; p<0.01), as was the iAUC for insulin (-56.48%, mean±SEM: 2559.9±255.2 μU/ml/min vs. 5883.5±479.0 μU/ml/min; p<0.001). Data were also analysed using a linear mixed model. A significant difference between consumption of the starch to which 10 g alpha-cyclodextrin was added and consumption of the control starch was found for T15-T90 min for glucose concentrations and for T30-T45 min for insulin concentrations. The Panel notes that this study shows an effect of alpha-cyclodextrin on reduction of post-prandial glycaemic responses without disproportionally increasing post-prandial insulinaemic responses.
The study by Gentilcore et al. (2011) was a double-blind, randomised cross-over study to investigate the effect of alpha-cyclodextrin on the gastric emptying of, and the glycaemic response to, an oral sucrose load. Thirteen subjects (median age 70 years, BMI 26.9 kg/m2) consumed a drink comprising 100 g sucrose dissolved in water, or 10 g of alpha-cyclodextrin added to 100 g sucrose before being dissolved in water (total volume of the drink 300 ml), with a wash-out period of at least seven days. Three subjects did not complete the study. Blood glucose and serum insulin concentrations were measured before and up to 300 min after consumption of the drink. Absolute values for blood glucose and serum insulin concentrations were analysed using repeated-measures two-way ANOVA followed by post hoc analyses of differences between treatments at each time point, corrected for multiple comparisons. No statistically significant difference in the iAUC for the glucose and insulin response between the control and the alpha-cyclodextrin group was shown. Peak blood glucose (p=0.88) and serum insulin (p=0.22) concentrations were not statistically significantly different between the control and alpha-cyclodextrin group. A significant treatment x time interaction (p<0.001) for blood glucose concentrations was observed. At t=60 min blood glucose was slightly greater (p<0.05) and at t=180 and 210 min slightly less (p<0.005) after the control drink when compared to alpha-cyclodextrin. The Panel notes that this study does not show an effect of alpha-cyclodextrin added to sucrose on reduction of post-prandial glycaemic responses.
With respect to the proposed mechanism, it was stated that due to the structural similarity of alpha-cyclodextrin to the helical parts of starch, alpha-cyclodextrin has an inhibitory effect on pancreatic amylase, and that alpha-cyclodextrin may also slow gastric emptying. It was also suggested that the post-prandial attenuation by alpha-cyclodextrin of the glycaemic and insulinaemic response is more pronounced if the meal contains starch rather than sucrose as the glycaemic component.
One human study (Gentilcore et al., 2011) which investigated the effects of alpha-cyclodextrin on gastric emptying, and two in vitro studies (Koukiekolo et al., 2001; Oudjeriouat et al., 2003) on the inhibitory effect of alpha-cyclodextrin on pancreatic alpha-amylase and barley amylase were provided in support of the proposed mechanisms.
The human intervention study by Gentilcore et al. (2011), as described above, also measured the amounts of the drink remaining in the total, proximal and distal stomach for up to 300 min after consumption of the drink, and the 50 % gastric emptying time (T50) was calculated. Gastric emptying time, expressed as AUC and T50, was not statistically significantly different between the control and the alpha-cyclodextrin group analysed using repeated-measures two-way ANOVA.
Kinetic studies have been carried out to determine the inhibitory effect of alpha-cyclodextrin on porcine pancreatic alpha-amylase using as amylose as the substrate (Koukiekolo et al., 2001). The inhibition of amylose hydrolysis by alpha-cyclodextrin was of competitive type with an inhibition constant of 7.0 mM. Kinetic studies have also been carried out to determine the inhibitory effect of alpha-cyclodextrin on barley alpha-amylase isozymes using DP-4900 amylose as the substrate (Oudjeriouat et al., 2003). alpha-Cyclodextrin was shown to be a weak inhibitor of barley alpha- amylase isozymes, compared to acarbose, a strong inhibitor of pancreatic alpha-amylase. Similar results were reported by Rejzek et al. (2011), where alpha-cyclodextrin was shown to have a weak inhibitor activity on barley β-amylase when soluble starch was used as the substrate.
Crystallographic analysis showed that three alpha-cyclodextrin molecules bind to the alpha-amylase enzyme, two of these in the active site cleft of the amylase and a third quite far from the active site, not associated with the substrate-binding cleft (Larson et al., 1994). alpha-Cyclodextrin is considered chemically identical to amylose and its cyclic structure resembles the six glycosyl-residue turn in the amylose helix. It is quite plausible that the association of alpha-amylose with cyclodextrins reflects the binding of helical turns of natural substrate (e.g. amylose). Using crystallographic analyses of porcine pancreatic alpha-amylase with alpha-cyclodextrin, a model for the binding of polysaccharides with a similar helical character as in natural substrates (i.e. starch and glucagon) was proposed (Larson et al., 2010).
The Panel notes that the proposed mechanism (inhibitory effect of alpha-cyclodextrin on pancreatic alpha-amylase) is in line with the evidence provided from the three intervention studies, i.e. two studies conducted with starch showed an effect of alpha-cyclodextrin on post-prandial glycaemic responses, whereas the study conducted with sucrose did not show such an effect.
In weighing the evidence, the Panel took into account that two intervention studies showed a significant effect of alpha-cyclodextrin added to starch on post-prandial glycaemic responses without disproportionally increasing post-prandial insulinaemic responses, that one study on alpha- cyclodextrin added to sucrose did not show an effect on post-prandial glycaemic responses, and that there is some evidence in support of a plausible mechanism by which alpha-cyclodextrin could exert the claimed effect.
The Panel concludes that a cause and effect relationship has been established between the consumption of alpha-cyclodextrin with starch-containing meals and reduction of post-prandial glycaemic responses.
